The US Preventive Services Task Force recommends referral to behavioral weight loss programs to help obese adults achieve a clinically meaningful weight loss of 8-10% of starting body weight. However, response heterogeneity is observed with half of participants unable to achieve this goal. Despite this heterogeneity, a one size fits all approach is the norm, a major drawback because non-response can in fact be detected early. This gap in weight loss intervention science calls for an adaptive intervention approach that could provide the right treatment at the right time for the right person. Adaptive interventions individualize treatment through empirically-supported decision rules advising when and how treatments should unfold over time to maximize effectiveness. Sequential Multiple Assignment Randomized Trials (SMART), developed explicitly to build optimal adaptive interventions, use experimental design principles to develop these decision rules. This application is responsive to PA-13-165: Innovative Research Methods: Prevention and Management of Symptoms in Chronic Illness and is the first we are aware of to apply this innovative methodological approach to adult weight loss. We propose a SMART to systematically evaluate therapeutic approach and timing variations for intervening with non-responders. Decisions about altering therapeutic strategy should take into consideration the reasons people struggle with weight loss. Self-regulation challenges have been identified as a major adherence barrier. Two attractive options to address self-regulation difficulties are: 1) augmenting behavioral treatment with Meal Replacements (MR) which decreases the need for self-regulation; and 2) switching therapeutic approaches by teaching acceptance and commitment skills (ACT) which boost capacity for self-regulation. Additionally, two time points for intervening with non-responders will be evaluated: 1) 5 weeks, based on emerging weight loss trial evidence; and 2) 10 weeks, based on average duration used in the extant stepped care literature. Adults (n=500) with 30 kg/m2 d BMI d 45 kg/m2 will be recruited and will receive individual behavioral weight loss treatment (BWL). Participants will be randomized to either: 1) treatment response assessment at 5 weeks or 2) treatment response assessment at 10 weeks. Participants identified as non-responders at Week 5 and Week 10 will be re-randomized to either: Augment with Meal Replacements or Switch to ACT. Participants identified as responders continue with BWL. All participants receive 6 months of intervention; research assessments take place at baseline, 6- and 18-months. The primary aim is to evaluate the benefit of augmenting treatment with MR's versus switching to ACT for non-responders. The secondary aim is to evaluate the optimal time to intervene with non-responders. These SMART results will lead to the empirically supported construction of an individualized adaptive intervention that will optimize weight loss outcomes and associated health benefits for obese adults.